AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning

AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver. Crat deletion in AgRP neurons increased peripheral fatty acid substrate utilization and attenuated the switch to glucose utilization after refeeding, indicating altered nutrient partitioning. Proteomic analysis in AgRP neurons shows that Crat regulates protein acetylation and metabolic processing. Collectively, our studies highlight that AgRP neurons require Crat to provide the metabolic flexibility to optimize nutrient partitioning and regulate peripheral substrate utilization, particularly during fasting and refeeding. Reichenbach et al. demonstrate that AgRP neurons require carnitine acetyltransferase to regulate peripheral substrate switching from fatty acid to glucose utilization during fasting and the transition to refeeding. This mechanism preserves fatty acids when glucose from food becomes available and maximizes energy conservation for future periods of energy deficit.